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Azatioprin

Klassificering: C

Preparat: Azathioprin 1A Farma, Azathioprin Actavis, Azathioprin Orifarm, Azathioprine, Azathioprine medac, Azatioprin Mylan, Imuran, Imuran®, Imurel®

ATC kod: L04AX01

Substanser: azatioprin, azatioprinnatrium

Sammanfattning

Studier har visat att män med Crohns sjukdom som behandlats med azatioprin har färre återfall i sjukdom än kvinnor.

En pediatrisk studie har visat att flickor med inflammatorisk tarmsjukdom som behandlats med azatioprin hade högre kvot mellan de potentiellt toxiska metaboliterna 6-MeMPN och 6-TGN än pojkar, vilket skulle kunna öka risken för lever- och blodbiverkningar. Monitorering av koncentration av azatioprin och dess metaboliter kan vara extra viktig hos flickor.

Additional information

Pharmacokinetics and dosing

Azathioprine is a prodrug to 6-mercaptopurine (6-MP), which has a major active metabolite, 6-TGN, and two inactive metabolites, 6-thiouracil and 6-methyl-mercaptourine (6-MeMPN).  High 6-TGN levels are responsible for myelotoxicity, while high levels of 6-MeMPN are associated with hepatotoxicity. A retrospective study has explored the weight-based dosage of azathioprine and the metabolite concentrations in pediatric patients with inflammatory bowel disease (45 boys, 41 girls). Multivariate analysis showed that girls had 36.3% higher 6-MeMPN/6-TGN ratio than boys [1]. No other studies with a clinically relevant sex analysis regarding the pharmacokinetics of azathioprine have been found.

Asian patients with Crohn disease might require lower doses of azathioprine than European patients. The efficacy of low-dose azathioprine (<1.0 mg/kg) in maintaining remission of Crohn disease in Chinese patients has been analyzed in a retrospective study of medical records (54 men, 23 women). The doses of azathioprine were adjusted according to efficacy and tolerance. A dose of <1.0 mg/kg azathioprine was more common in men [2]. A possible explanation could be that higher rates of relapse have been observed in female patients with Crohn disease [3, 4], and their doses have been escalated.

Effects

Long-term follow-up of patients with Crohn disease treated with azathioprine or 6-mercaptopurine has been evaluated retrospectively (68 men, 89 women). Patients were treated with azathioprine or 6-mercaptopurine for >6 months and were in clinical remission. Women had a higher risk of relapse during the drug treatment (risk ratio 2.3; 95% CI: 1.0-5.1), while men had higher risk after drug withdrawal (risk ratio 5.2; 95%CI 2.2-12.0). Therefore, the authors assumed that patients who received the greatest benefit from the drug (i.e. men) were also more affected by drug withdrawal [3]. The better outcome in men with Crohn disease was also found in another study of patients with inflammatory bowel disease. Patients had been treated with azathioprine for >6 months [4].In some countries, azathioprine is used in monotherapy for severe atopic dermatitis in adult and pediatric patients. A study has reviewed the clinical efficacy of azathioprine in children with atopic dermatitis (9 boys, 8 girls; mean age 16.1 years). At 3 months, there were no differences in efficacy between boys and girls. At 6 months, girls had lower disease activity score than boys (28.4 vs. 46.8). The reason for this sex differences is unclear [5].In a double-blind controlled trial, multiple sclerosis patients (11 men, 19 women) were given prednisolone and azathioprine (3 mg/kg per day) for 15 months. Number of relapses during the study period was lower among patients receiving treatment and among women. However, the authors assumed that the results were more striking in women due to the small number of treated men [6].

Adverse effects

A retrospective study has explored the weight-based dosage of azathioprine and the metabolite concentrations in pediatric patients with inflammatory bowel disease (45 boys, 41 girls). Multivariate analysis showed that girls had 36.3% higher 6-MeMPN/6-TGN ratio than boys. This might mean that girls develop azathioprine-induced hepatotoxicity and myelotoxicity more readily than boys. Therefore, the authors suggest that monitoring of drug concentrations are of high importance in azathioprine-treated girls with inflammatory bowel disease [1].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Försäljning på recept

Något fler kvinnor än män hämtade ut tabletter innehållande azatioprin (ATC-kod L04AX01) på recept i Sverige år 2015, totalt 9 306 kvinnor och 8 863 män. Det motsvarar 1,9 respektive 1,8 personer per tusen invånare. Andelen som hämtat ut läkemedel var högst i åldersgruppen 55-74 år hos kvinnor och i åldersgrupperna 25-44 år och 65-74 år hos män. I genomsnitt var tabletter innehållande azatioprin 1,1 gånger vanligare hos kvinnor [7].

Uppdaterat: 2019-02-26

Litteratursökningsdatum: 2015-06-22

Referenser

  1. Nguyen TV, Vu DH, Nguyen TM, Lachaux A, Boulieu R. Relationship between azathioprine dosage and thiopurine metabolites in pediatric IBD patients: identification of covariables using multilevel analysis. Ther Drug Monit. 2013;35:251-7. PubMed
  2. Wu J, Gao Y, Yang C, Yang X, Li X, Xiao S. Low-dose azathioprine is effective in maintaining remission among Chinese patients with Crohn's disease. J Transl Med. 2013;11:235. PubMed
  3. Bouhnik Y, Lémann M, Mary JY, Scemama G, Taï R, Matuchansky C et al. Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Lancet. 1996;347:215-9. PubMed
  4. Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut. 2002;50:485-9. PubMed
  5. Hon KL, Ching GK, Leung TF, Chow CM, Lee KK, Ng PC. Efficacy and tolerability at 3 and 6 months following use of azathioprine for recalcitrant atopic dermatitis in children and young adults. J Dermatolog Treat. 2009;20:141-5. PubMed
  6. Mertin J, Knight SC, Rudge P, Thompson EJ, Healy MJ. Double-blind, controlled trial of immunosuppression in treatment of multiple sclerosis. Lancet. 1980;2:949-51. PubMed
  7. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-04-05.] länk

Författare: Linnéa Karlsson Lind, Desirée Loikas

Faktagranskat av: Mia von Euler

Godkänt av: Karin Schenck-Gustafsson